Tuning GABAa receptors, plus Oxytocin

Today’s post will hopefully not get too complicated.

As has been mentioned in this blog, and also at leading institutions like MIT, it does seem possible to fine-tune certain receptors in the brain that have become dysfunctional in autism.  In the case of MIT they were “tuning” a receptor called mGluR5, which they suggested was either hypo or hyper, in other words too much or too little, depending on what the underlying disease variant was.

This was done with something called an allosteric modulator, either a positive one called PAM, or a negative one called NAM.

They found that a particular glumate receptor, called mGluR5, was dysfunction in many autism-like conditions.  But the nature of the dysfunction varied, so different people would require different treatments to return the receptor performance back to normal (top dead center).   So it really becomes like tuning your car engine. 

As I have progressed in my review of the literature it becomes clear that numerous receptors are “out of tune”; so a better analogy is tuning something like a piano.

  

Ketamine, Memantine, D-Cycloserin, Magnesium, Fenobam and yet more as Glutamatergic Modulators in Autism (and Fragile X)

"Tuning" the shape (but not number) of dendritic spines also appears not to be as fanciful as it sounds.

Back to GABA_A

Regular readers will know that one of the key dysfunctional receptors in autism is called GABA_A.

GABA A Receptors in Autism – How and Why to Modulate Them

This subject is very complicated.  In effect what appears to have happened in autism is that the neurons have not matured as they should, and so GABA_A receptors continue to function in their “normal” immature state.  The concentration of chloride remains high since the NKCC1 transporter continues to exist, whereas KCC2/3 should have developed.  The result is that when the receptor is stimulated, instead of causing an inhibitory/calming effect it causes an excitatory effect.

This is fortunately treatable by inhibiting the flow of chloride into the cells, through NKCC1, using a drug called Bumetanide.

However this is not the end of the story.

At least 11 binding sites on GABA_A receptors

As you can learn from Wikipedia:-

The active site of the GABA_A receptor is the binding site for GABA and several drugs such as muscimol, gaboxadol, and bicuculline. The protein also contains a number of different allosteric binding sites which modulate the activity of the receptor indirectly. These allosteric sites are the targets of various other drugs, including the benzodiazepines, nonbenzodiazepines, barbiturates, ethanol, neuroactive steroids, inhaled anaesthetics, and picrotoxin, among others.

We are particularly interested in the allosteric binding sites.

The only one that is usually referred to, in any depth, is the site for benzodiazepines, but there are at least 11 different binding sites.

GABAa receptor pharmacology.

Abstract

gamma-Aminobutyric acid (GABA)a receptors for the inhibitory neurotransmitter GABA are likely to be found on most, if not all, neurons in the brain and spinal cord. They appear to be the most complicated of the superfamily of ligand-gated ion channels in terms of the large number of receptor subtypes and also the variety of ligands that interact with specific sites on the receptors. There appear to be at least 11 distinct sites on GABAA receptors for these ligands.

Development of Subtype-Selective GABAA Receptor Compounds for the Treatment of Anxiety, Sleep Disorders and Epilepsy

These sites include:-

·        GABA Binding Site

·        Benzodiazepine Binding Site

·        Neurosteroid Binding Site

·        Convulsant Binding Site

·        Barbiturate Binding Site

·        b Subunit Binding Site(s)

In an earlier post I highlighted the discovery by Professor Catterall, that tiny doses of a particular Benzodiazepine drug called Clonazepam had a strange effect on the GABA_A receptor.

Clonazepam is a known Positive Allosteric Modulator (PAM) of the GABA_A site.  In mature neurons it amplifies the calming effect when the GABA binding site is stimulated.  In mouse models of autism (we assume therefore immature neurons)   where GABA is still excitatory, the tiny dose seemed to switch it to inhibitory.

This suggests a new function, rather than a PAM, the effect was to invert the function entirely.

Now it appears that similar things may indeed also be possible at some of the other 9+ binding sites (I exclude GABA Binding Site itself)

As complicated as this subject may sound, it actually gets even more complicated since the GABA receptors are made up of sub-units.  It appears that mutations in these subunits may be a cause of some epilepsies and, I propose, some “oddities” in autism.

Recent studies have again shown that many genetic dysfunctions found in autism relate to GABA, this short article is not so recent, but gives a nice summary:-

GABA is the major inhibitory neurotransmitter in the brain. It essentially acts as a brake for brain activation. Several aspects of GABA regulation have been linked to ASD, from early brain development to adult brain function.

Variations in GABA receptor subunits have been strongly associated with ASD. GABA receptors come in two major forms: fast, “ionotropic” GABAA receptors let negatively charged chloride ions flow into the neuron, and slow, “metabotropic” GABAB receptors produce chemical messages inside the neuron. GABAA receptors, the most common form in the brain, contain five subunits that shape their properties. Genome-wide association studies have linked the GABAA receptor subunit genes GABRA4 (α4 subunit), GABRB1 (β1 subunit), and GABRB3 (β3 subunit) to autism.[1][2] In addition, deletion of a chromosomal region that contains a cluster of a variety of GABA receptor genes (region 15q11-13) causes Angelman Syndrome.[3][4]

Genes controlling the development of GABA-releasing neurons have also been associated with ASD. Autism-linked variations in the ARX and DLX family of transcription factors interfere with proper expression of GABA.[5][6][7] Absence of such GABA-releasing neurons would negatively affect early brain development as well as adult brain stability.

Notably, variations in other ASD-linked genes affect GABA signaling. New evidence shows that the gene MECP2, the mutation of which causes Rett Syndrome, is critical for normal function of GABA-releasing neurons.[8] When MECP2 expression was blocked in GABAergic neurons of mice, GABA expression and release were reduced and the mice exhibited autistic behaviors.

ASD is a complex disorder that is likely to be caused by a combination of mutations in a variety of genes. GABA receptors are a promising therapeutic target because of their important role in monitoring brain excitation. Identification and exploration of autism-linked mutations in other GABA-related genes could shed light on the pathogenesis of autism.

Over to Switzerland

At the University of Bern a small research group is looking  at the world of  GABA_A receptors, here is what they say:-

“Many scientists and companies are put off by the complexity of the field of GABA_A receptors, but it is exactly this complexity that offers numerous possibilities of fine-tuned pharmacological interventions.” 

Prof.Dr. Erwin Sigel

Here is one of their recent papers, that shows both what is known and how very much remains unknown.

Structure, Function, and Modulation of GABAA Receptors

Ion Conductance

The GABA_A receptors are generally GABA-gated anion channels selective for Cl⁻ ions, with some permeability for bicarbonate anions (49). Exceptionally, in C. elegans, a cation-selective GABA-gated channel has been discovered (50). Excitatory neurotransmitters increase the cation conductance to depolarize the membrane, whereas inhibitory neurotransmitters increase the anion conductance to tendentially hyperpolarize the membrane. However, if the gradient for Cl⁻ ions decreases due to down-regulation of KCC2 chloride ion transporters, opening of GABA_A receptors may cause an outward flux of these anions, leading to depolarization of the membrane and thereby to excitation. This phenomenon has been implicated in neuropathic pain (51). During early development (52) and in neuronal subcompartments (53), GABA similarly confers excitation. 

Although it is relatively simple to address questions at the level of individual receptor subunit isoforms, we can only speculate how many GABA_A receptors are expressed in our brain and what their subunit composition is, not to mention subunit arrangement.

Conclusions

Many scientists and companies are put off by the complexity of the field of GABA_A receptors, but it is exactly this complexity that offers numerous possibilities of fine-tuned pharmacological interventions.

It may be anticipated that genetic alterations of subunits of the GABA_A receptor affect any of the above mentioned processes and thereby contribute to inherited human diseases. A start has been made with the analysis of point mutations that cause epilepsy

Mutations in GABAA receptor subunits associated with genetic epilepsies

Why is all this relevant ?

We have in recent posts discovered that at least two anti-convulsants (carbamazepine and phenytoin) appear to modulate GABAA receptors in unexpected ways when given in tiny doses.

We also found out that valproate also seems to possess such qualities.  The exact mode of action of valproate is not known and perhaps it also acts a modulator of one of the many binding sites on the GABAA receptors.

We do think that valproate is working somehow via GABA.

Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin

It turns out that Carbamazepine has also been shown to potentiate GABA receptors made up of alpha1, beta2, and gamma2 subunits.

I have already established that the effect of tiny doses of Valproate is not the same as tiny doses of Clonazepam.

The next step would be to look at the effect of tiny doses of carbamazepine, phenytoin and potentially anything else that modulates those mysterious  GABA_Asites.  They are clearly all there for a reason.  It seems that their role goes beyond just the allosteric modulation (amplification/reduction) of GABA’s effect.  It is likely much more subtle and they affect emotional behaviour.

Given the difficulty/impossibility of research on human brains, in the end we may need to revert to the medical world’s often used “scientific” discovery methods known as trial and error, and stumbled upon.

For the moment that will be left to Professors Sigel and Catterall and their mice, and Dr Bird, in Australia, with his human subjects.

Oxytocin and Bumetanide share the same mode of action in autism

Whilst on the subject of GABA_A, I should come back to Oxytocin.

Oxytocin-Mediated GABA Inhibition During Delivery Attenuates Autism Pathogenesis in Rodent Offspring

The conclusion of this Ben-Ari paper from last year is that Oxytocin and Bumetanide share the same effect in autism; they lower the level of chloride within the neurons and help switch GABA back to inhibitory.

It seems that oxytocin from the mother may be the signal to the developing brain to lower Cl levels.  Oxytocin has many other functions in the body.

Small doses of oxytocin/Syntocinon, have been shown to be effective in some people with autism.  One reader from Portugal has written on this blog how effective it has been in his young son.

Oxytocin/Syntocinon is not available everywhere, but is being reintroduced to the US.

Retrophinto reintroduce Syntocinon™ Nasal Spray in the U.S. and Develop the Drug for Schizophrenia and Autism

I am wondering if in some people, who are not responders, bumetanide/oxytocin lowers the level of chloride, but not enough to show any benefit.  People using Bumetanide, which has a short half-life, comment that the effect fades through the day and that splitting the same daily dose 3 times a day is beneficial over 2 times a day.  This might suggest that combining Oxytocin with Bumetanide might give better results, by maintaining the downward pressure on chloride levels and keeping GABA more inhibitory and for longer.

In the longer term, an analog of Bumetanide is needed without the diuretic effect and with a delayed release, to maintain a constant effective level.  This is known to the researchers, but would require a big financial investment.

Larger doses of oxytocin are likely to produce effects elsewhere in the body.

If anyone tries the combination of Bumetanide + oxytocin, let me know.

GABA’s role in Neurodevelopment – Oxytocin and Bumetanide

This is a very brief post to direct those of you interested in the role of GABA, the neurotransmitter, towards a very recent open access review paper by Ben Ari.

In particular, people considering Oxytocin or Bumetanide to treat autism may find it interesting.

The GABA excitatory /inhibitory developmental sequence: a personal journey

Central Serotonergic Hypoactivity in Autism & Degradation of Tryptophan

 

Today’s post has an impressive title and a year ago I would not have understood it, but it summarizes exactly what may be going on inside the autistic brain.  It fits into the wider puzzle of hormonal imbalances in autism that then manifest themselves into behaviours ranging from qwerky to extreme self-injury.

Human emotions and behaviours are influenced by parallel signals from the nervous system (i.e. the brain) and the endocrine system.  The two systems are interconnected and so your state of mind in controlled by hormones that you cannot directly control and the nervous system which you can learn to control.  For example, you can make yourself happy, unhappy, or depressed with the power of your mind.  You can train yourself to overcome fear.  Some people are clearly very much better at doing this than others; but the potential to do so lies within all of us, autistic or neurotypical.  This also explains why singing makes you happy and rapidly reduces cortisol, your stress hormone, as we learnt in an earlier post.

So on the one hand we need to understand any in-built hormonal disturbances in autism and then see how to best tackle them using the hormonal system and the nervous system.  This may sound like fantasy but the more you learn about it, the more plausible it becomes.

Serotonin

Most people have heard of Serotonin; it is frequently thought of as the “happy hormone”.

As we have learnt in this blog, the human body is not like any man-made invention, it seems to function in quite irrational ways.  Serotonin is found mainly in the intestines and less than 10% is in the brain (and CNS), but it is not the same serotonin.  Serotonin cannot cross the blood brain barrier.  In autism serotonin in the blood (produced in the intestines) tends to be elevated, but the level of serotonin in the brain appears to be reduced.  So there appears to be a failure in the entire serotonin system, the one for the brain and the one for the blood.

Drugs that lower brain serotonin are often used to treat the symptoms of autism.  Even Temple Grandin admits (on her own website) to being on a low dose of Prozac to control her anxiety.  In spite of a long list of side effects, many children with ASD living in the US are prescribed this serotonin lowering drug.  Prozac is a heavily prescribed antidepressant drug and is a selective serotonin reuptake inhibitor (SSRI).

Somewhat bizarrely, Prozac is linked to an increase in suicidal tendencies.  As is often the case, many drugs have secondary or tertiary modes of action; you will experience all of them.

In the language of your doctor, low brain serotonin would be called central serotonergic hypoactivity, but don’t go asking him to test it, because he cannot.  All he can do is measure the level of serotonin in the blood or urine, and probably tell you that it is slightly elevated and not to worry.

Researchers have known about this serotonin paradox in autism for many years.  To my surprise a researcher at Yale University even made a mathematical model to better understand it. 

Serotonergic paradoxes of autism replicated in a simple mathematical model

Since the early 1960s, the most consistent pathophysiological finding in autistic individuals has been their statistically elevated blood 5-hydroxytryptamine (5-HT, serotonin) levels. However, many autistic individuals have normal blood 5-HT levels, so this finding has been difficult to interpret. The serotonin transporter (SERT) controls 5-HT uptake by blood platelets and has been implicated in autism, but recent studies have found no correlation between SERT polymorphisms and autism. Finally, autism is considered a brain disorder, but studies have so far failed to find consistent serotonergic abnormalities in autistic brains. A simple mathematical model may account for these paradoxes, if one assumes that autism is associated with the failure of a molecular mechanism that both regulates 5-HT release from gut enterochromaffin cells and mediates 5-HT signaling in the brain. Some 5-HT receptors may play such a dual role. While the failure of such a mechanism may lead to consistent abnormalities of synaptic transmission with no alteration of brain 5-HT levels, its effects on blood 5-HT levels may appear paradoxical.

 The figure below sums up what appears to be going wrong.

 

A great all-in-one overview

If you only want to read one paper on serotonin and autism, and one that is not too science heavy, the one for you is:-

A review of the serotonintransporter and prenatal cortisol in the development of autism spectrum disorders

If you have more interest, then read on …

Research on Serotonin in the Autistic Brain

A recurring problem in all brain research is the lack of physical samples.  You cannot just open up someone's head and take a brain biopsy.  Research is either carried out on the tiny number of autistic brains donated to medical research, or it is non-invasive (MRIs and EEGs etc.), or it is very indirect.  An example of this latter type is the following paper from Belgium, home of kriek, a beer made from cherries and French fries served with mayonnaise.

Central serotonergic hypofunction in autism: results of the 5-hydroxy-tryptophan challenge test.

"Some studies have suggested that disorders in the central serotonergic function may play a role in the pathophysiology of autistic disorder. In order to assess the central serotonergic turnover in autism, this study examines the cortisol and prolactin responses to administration of L-5-hydroxy-tryptophan (5-HTP), the direct precursor of 5-HT in 18 male, post-pubertal, Caucasian autistic patients (age 13-19 y.; I.Q.>55) and 22 matched healthy volunteers. Serum cortisol and prolactin were determined 45 and 30 minutes before administration of 5-HTP (4 mg/kg in non enteric-coated tablets) or an identical placebo in a single blind order and, thereafter, every 30 minutes over a 3-hour period. The 5-HTP-induced increases in serum cortisol were significantly lower in autistic patients than in controls, whereas there were no significant differences in 5-HTP-induced prolactin responses between both study groups. In baseline conditions, no significant differences were found in serum cortisol and prolactin between autistic and normal children. The results suggest that autism is accompanied by a central serotonergic hypoactivity and that the latter could play a role in the pathophysiology of autism."

 

Tryptophan and DHEA

Just to complicate things a little further, I now introduce you to Tryptophan and DHEA.

Tryptophan is an essential amino acid, meaning that it is essential for human life, cannot be synthesized by the organism, and therefore must be part of your diet.

Tryptophan functions as a biochemical precursor for the following compounds:

• Serotonin, synthesized via tryptophan hydroxylase. Serotonin, in turn, can be converted to melatonin (a  neurohormone).
• Niacin is synthesized from tryptophan via kynurenine and quinolinic acids as key biosynthetic intermediates
• Auxin (a phytohormone) when sieve tube elements undergo apoptosis tryptophan is converted to auxins

The disorders fructose malabsorption and lactose intolerance cause improper absorption of tryptophan in the intestine, reduced levels of tryptophan in the blood and depression

What you will not find on Wikipedia, is that perhaps Tryptophan is in fact also a bona fide neurotransmitter in its own right.

Tryptophan as an evolutionarily conserved signal to brain serotonin: molecular evidence and psychiatric implications.

Abstract

The role of serotonin (5-HT) in psychopathology has been investigated for decades. Among others, symptoms of depression, panic, aggression and suicidality have been associated with serotonergic dysfunction. Here we summarize the evidence that low brain 5-HT signals a metabolic imbalance that is evolutionarily conserved and not specific for any specific psychiatric diagnosis. The synthesis and neuronal release of brain 5-HT depends on the concentration of free tryptophan in blood and brain because the affinity constant of neuronal tryptophan hydroxylase is in that concentration range. This relationship is evolutionarily conserved. Degradation of tryptophan, resulting in lower blood levels and impaired cerebral production and release of serotonin, is enhanced by inter alia inflammation, pregnancy and stress in all species investigated, including humans. Consequently, tryptophan may not only serve as a nutrient, but also as a bona fide signaling amino acid. Humans suffering from inflammatory and other somatic diseases accompanied by low tryptophan levels, exhibit disturbed social behaviour, increased irritability and lack of impulse control, rather than depression. Under particular circumstances, such behaviour may have survival value. Drugs that increase brain levels of serotonin may therefore be useful in a variety of psychiatric disorders and symptoms associated with low availability of tryptophan. 

This paper is open access, it gets quite technical but here is a summary of the conclusion. 

Decreased tryptophan metabolism in patients with autism spectrum disorders

 

Our findings support a possible mitochondrial dysfunction as a result of impaired tryptophan metabolism in cells from patients with ASDs

Although approximately 99% of the dietary tryptophan intake is metabolized via the kynurenine pathway, tryptophan is also the main precursor for both serotonin and melatonin

Melatonin plays a critical role in the regulation of the circadian rhythm, and anomalies of this rhythm have been associated with some of the signs in the autistic spectrum, like seizures or sleep disorders

Serotonin is a neurotransmitter involved in multiple aspects of brain functions, ranging from the regulation of mood to the control of appetite and social interactions and its production has been reported as deficient in ASD brains.

Tryptophan levels have been demonstrated to directly influence central nervous system (CNS) serotonin levels and behavior, and altered tryptophan transport has been described in fibroblasts from boys with attention deficit/hyperactivity disorder (ADHD)

Patients with ASDs, on average, are less capable of utilizing tryptophan as an energy source than controls.

Decreased tryptophan metabolism in patients with ASDs may alter metabolic pathways involved in the regulation of the early stages of brain development (first month of gestation), mitochondrial homeostasis and immune system activity in the brain.

Disruption of such pathways can primarily be caused either by insufficient serotonin production by placental cells, mitochondrial dysfunction and/or impaired balance between quinolinic and kynurenic acid in fetal cells. The combined effects of these events could lead to abnormal organization of neurons , particularly in specific brain regions, determining the imbalance between the short- and long-term circuitry that has been considered to be one of the fundamentals of the ASD neuropathology

Even though the ideal target tissue, brain, could not be investigated, our observation of decreased tryptophan metabolism in cells from patients with ASDs may provide a unifying model that could help explain the genetic heterogeneity of ASDs.

Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD⁺, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs.

DHEA

DHEA  (didehydroepiandrosterone) It is the most abundant circulating steroid in humans, importantly for us to know it is also produced in the brain.  It has a variety of potential biological effects in its own right, binding to an array of nuclear and cell surface and acting as a neurosteroid.

Faulty serotonin--DHEA interactions in autism: results of the5-hydroxytryptophan challenge test. 

Abstract

BACKGROUND:

Autism is accompanied by peripheral and central disorders in the metabolism of serotonin (5-HT). The present study examines plasma dehydroepiandrosterone-sulphate (DHEA-S) and the cortisol/DHEA-S ratio following administration of L-5-hydroxytryptophan (5-HTP), the direct precursor of 5-HT, to autistic patients.

METHODS:

Plasma DHEA-S levels were determined both before and after administration of 5-HTP or placebo, on two consecutive days in a single blind order in 18 male autistic patients and 22 matched healthy controls.

RESULTS:

The 5-HTP-induced DHEA-S responses were significantly higher in autistic patients than in controls. In baseline conditions, the cortisol/DHEA-S ratio was significantly higher in autistic patients than in controls. Discussion: The results suggest that autism is accompanied by a major disequilibrium in the serotonergic system. The increased Cortisol (neurotoxic) versus DHEA-S (neuroprotective) ratio suggests that an increased neurotoxic potential occurs in autism.

CONCLUSIONS:

It is concluded that disequilibrium in the peripheral and central turnover of serotonin and an increased neurotoxic capacity by glucocorticoids are important pathways in autism.

 

Mice Studies

For the mice lovers amongst you, they also get their vitamin P (Prozac).

Serotonin Defects Identified in "Autistic" Mice

 

Serotonin modulators mitigate some BTBR behaviors

The researchers tested the effects of acute doses of fluoxetine (Prozac) (an SERT blocker), risperidone (a 5-HT_2A receptor antagonist), and buspirone (a partial 5-HT_1A receptor agonist) on social and repetitive behaviors of BTBR mice. These three compounds regulate serotonin activity and have inconsistent, limited, and sometimes harmful effects in rodent models of and people with autism. Only buspirone and fluoxetine were found to make BTBR mice significantly more social: treated mice spend proportionally more time socializing with a strange mouse than do saline-treated controls. Interestingly, BTBR mice treated with either buspirone or fluoxetine show a reduced interest in social novelty: when introduced to a second stranger mouse, they do not show a preference for either stranger. In contrast, the saline-treated controls spend more time investigating the newer mouse. Compared to either buspirone- or fluoxetine-treated mice and saline-treated controls, Risperidone-treated mice spend less time investigating strange mice and novel surroundings.

Regardless of treatment, BTBR mice spend comparable amounts of time burying marbles (an index of repetitive behavior). However, eliminating from the analysis one saline-treated control that did not bury any marbles suggests that risperidone-treated mice bury significantly fewer marbles than the saline-treated controls.

In summary, Daws and her team concluded that the autism-like behaviors of BTBR mice are likely due in part to an altered hippocampal SERT serotonin transporter and/or an altered 5-HT_1A serotonin receptor. These findings may lead to the identification of additional therapeutic targets for treating human autism.

 

Conclusion

There was a lot of science in this post and it was clear that the mechanisms involved are only very partially understood by researchers.

It is clear that interventions increasing central (brain) serotonin levels are likely to reduce autistic behaviours.  Prozac was mentioned, but there is a much wider class of drugs called serenic, many of which could potentially be helpful.  As mentioned earlier, the big problem with most of the drugs created for psychiatrists is side effects.  Autism is supposed to be very common, but you would not think so by looking at way new drugs are developed.  As a result, the drugs currently used in ASD and the majority of those in the pipeline are ones developed for other conditions (depression, bi-polar, psychosis , anxiety, ADHD, schizophrenia, Alzheimer’s etc.) many of which share some similar characteristics, but are essentially different conditions, with the exception of ADHD.  It is akin to trying to fix your Ford car with a parts bin filled with Toyota components; it is possible, but not a wise idea.

In my opinion, all the hormone dysfunctions in autism can eventually be traced back to damage caused by oxidative stress and neuroinflammation.  The brain has just adjusted to find a new homeostasis, which happens to be an autistic one.  The list of metabolic disturbances in autism is long and getting longer; but they are just consequences.  I very much doubt it is ever going to be possible to go hormone by hormone, neurotransmitter by neurotransmitter “correcting” them.   I think the best solution is to go further back up the chain and look at how hormones and neurotransmitters themselves are jointly regulated.  I do not believe anyone fully understands the molecular basis on which this is carried out, but as I have pointed out earlier in this blog, you can get the right answer for the wrong reasons and also without showing your workings.  As long as it works, perhaps understanding why does not matter.  A much less intellectual approach might indeed prove effective.

I will continue with my problem solving, but less intellectual, approach and see where it leads.

 
P.S.
 
Just to show how all the hormones are interrelated, I added the paper below from Japan.  They investigate the relationship between Oxytocin and Serotonin:

Evidence That Oxytocin Exerts Anxiolytic Effects via Oxytocin Receptor Expressed in Serotonergic Neurons in Mice

"It is thus possible that oxytocin modulates not only anxiety-related behavior but also social behavior via serotoninergic transmission. These observations may provide new insights into psychiatric disorders associated with disruptions in social and emotional behavior, including autism, anxiety disorders, and depression."

 

Oxytocin - Not to be sniffed at?

Things seem to move slowly in the world of autism research.

Since the 1970s it has been discussed that oxytocin might be a wonder hormone that could make you feel better.  The problem was that it cannot cross the BBB (blood brain barrier).  Oxytocin secreted from the pituitary gland cannot re-enter the brain because of the BBB. Instead, the behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland.

Oxytocin is destroyed in the gastrointestinal tract, so must be administered by injection or as a nasal spray.  Because of the BBB any injected oxytocin should fail to enter the brain.  The nasal method of delivery uses the nasal membrane as a means of transferring the oxytocin.  But when it passes through that membrane it surely enters the blood and then will struggle to cross the BBB.  Note that most of oxytocin’s primary functions are outside of the brain; the ones relevant to autism however occur inside the brain.

For several years it was assumed that the nasal spray oxytocin could not possible affect behaviours, since it could not enter the brain.  This view now seems to be in question.  It seems fair to assume that either a small portion of the oxytocin manages to cross the BBB, or perhaps the BBB is indeed more permeable in some people.  There is a school of thought that believes that autism is caused by a BBB malfunction, and certain harmful substances that should have been kept out of the brain, were let in.  If this were indeed the case, perhaps that faulty BBB would also let the oxytocin in?

I had rather assumed that after 30-40 years, if there was some element of truth in the therapeutic value of oxytocin, it would have been proved by now.

The Good(ish) News

A five year study of the benefits of oxytocin nasal spray in autism will start this year in the US at some leading hospitals including Massachusetts General Hospital.  The study is managed by researcher Dr Linmarie Sikich, MD of the ASPIRE Research Program at the University of North Carolina-Chapel Hill.  The study will have 300 participants.

It is a follow-on study to one already completed by Dr Sikich and funded in part by Autism Speaks.  This initial study involved just 25 children, but seemed to have a positive outcome.

The Science Part

As I mentioned, there has been a great deal of research into Oxytocin.  Here is free paper called Social effects of oxytocinin humans: context and person matter.

A study was carried out in 2012 on adults with autism; the researchers did not seem to be that excited about the results, but suggested that the results warranted further studies.  The study is free to access:  Intranasal oxytocin versus placebo in the treatment of adults with autismspectrum disorders: a randomized controlled trial

A more typical study is this one:- Oxytocin, vasopressin and pair bonding: Implications for autism.  It sounds interesting, but in fact is more about the mating patterns of prairie voles vs. meadow voles.

In 2003 a study using an infusion of oxytocin vs. a placebo looked at the effects on repetitive behaviours:-  Oxytocin Infusion Reduces RepetitiveBehaviors in Adults with Autistic and Asperger’s Disorders

 
I wish these scientists would decide once and for all if oxytocin can cross the BBB.  If it cannot, then a huge amount of time and money is being wasted.

 

Conclusion

It seems that oxytocin spray does not appear to do harm.  It is already available over the counter (OTC) and indeed over the internet.  If you take too much oxytocin, some pretty strange things will start happening, since it is a hormone with many specific roles in the human body, other than making you feel good.

Some researchers and parents seem very impressed by its effects on autistic subjects.  Other scientists think it cannot possibly cross into the brain.

In five years’ time we should know conclusively whether it really does “work”.

 
I would put it in my plausible, but not proven, category. 

If you do try it at home, do let us all know the results.